Regulation of gene expression by MF63, a selective inhibitor of microsomal PGE synthase 1 (mPGES1) in human osteoarthritic chondrocytes
| Autor: | Teemu Moilanen, Lauri Tuure, Mari Hämäläinen, Antti Pemmari, Eeva Moilanen |
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| Přispěvatelé: | Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Tampere University |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine medicine.medical_treatment chondrocytes Gene Expression Arthritis Osteoarthritis Pharmacology prostaglandins 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Microsomes Gene expression medicine Humans Metallothionein Cells Cultured Prostaglandin-E Synthases mPGES‐1 Regulation of gene expression Chemistry Prostaglandins E Cartilage Prostanoid mPGES-1 medicine.disease Research Papers Intramolecular Oxidoreductases osteoarthritis 030104 developmental biology Cytokine medicine.anatomical_structure Gene Expression Regulation gene expression Female 030217 neurology & neurosurgery Research Paper Farmasia - Pharmacy |
| Zdroj: | British Journal of Pharmacology |
| Popis: | BACKGROUND AND PURPOSE mPGES1 catalyses the production of PGE2 , the most abundant prostanoid related to inflammation and pain in arthritis. mPGES1 is suggested to be a safer and more selective drug target in inflammatory conditions compared to the COX enzymes inhibited by NSAIDs. In the present study, we investigated the effects of the selective mPGES1 inhibitor MF63 on gene expression in primary human chondrocytes from patients with osteoarthritis (OA). EXPERIMENTAL APPROACH Chondrocytes were isolated from articular cartilage obtained from osteoarthritis patients undergoing knee replacement surgery. The effects of MF63 were studied in the primary chondrocytes with RNA-sequencing based genome-wide expression analysis. The main results were confirmed with qRT-PCR and compared with the effects of the NSAID ibuprofen. Functional analysis was performed with the GO database and interactions between the genes were studied with STRING. KEY RESULTS MF63 enhanced the expression of multiple metallothionein 1 (MT1) isoforms as well as endogenous antagonists of IL-1 and IL-36. The expression of IL-6, by contrast, was down-regulated. These genes were also essential in functional and interaction network analyses. The effects of MF63 were consistent in qRT-PCR analysis, whereas the effects of ibuprofen overlapped only partly with MF63. There were no evident findings of catabolic effects by MF63. CONCLUSION AND IMPLICATIONS Metallothionein 1 has been suggested to have anti-inflammatory and protective effects in cartilage. Up-regulation of the antagonists of IL-1 superfamily and down-regulation of the pro-inflammatory cytokine IL-6 also support novel anti-inflammatory and possibly disease-modifying effects of mPGES1 inhibitors in arthritis. |
| Databáze: | OpenAIRE |
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